- Email: [email protected]
Positive margins after partial nephrectomy in renal cell carcinoma: Oncological outcomes of conservative management after long-term follow-up
Actas Urol Esp. 2019;43(8):414---418
Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro
ORIGINAL ARTICLE
Positive margins after partial nephrectomy in renal cell carcinoma: Oncological outcomes of conservative management after long-term follow-up夽 J.J. Fernández-Concha Schwalb ∗ , J.I. Pérez Reggeti, M.A. López Costea, X. Bonet Puntí, H. Ramos Reina, F. Vigués Julia Servicio de Urología, Hospital Universitario de Bellvitge, Barcelona, Spain Received 14 January 2019; accepted 4 March 2019 Available online 20 September 2019
KEYWORDS Partial nephrectomy; Renal cell carcinoma; Positive margins
Abstract Introduction: Partial nephrectomy (PN) is the standard treatment for small and localized kidney tumors (cT1). One of the controversial aspects regarding this technique is the management of affected/positive resection margins. We present the long-term oncological results in patients with PSM after PN managed conservatively. Material and methods: There were 207 PN performed in our center between 1990 and 2011. 17 patients presented PSM. 2 patients were excluded from the study due to completion nephrectomy afterwards. Follow-up was done with abdominal contrast-enhanced computed tomography every 6 months for the first 2 years and subsequently, once a year. Cancer-specific survival and disease-free survival were calculated with the Kaplan---Meier method. Results: The median age was 62 years (RIQ: 55---71) and the mean tumor size was 34.8 (10---77) mm. Histopathological results were: 6 (40%) clear cell RCC, 4 (26.7%) papillary, 3 (20%) chromophobe and 2 (13.3%) oncocytic. The pathologic stages were: 11 (73.3%) pT1a, 1 (6.7%) pT1b and 3 (20%) pT3a. The median follow-up was 84 months (IQR 72---120). 2 patients had metastatic recurrence and this was the cause of death. The first one had recurrence at 112 months and the second one at 59. 5-year CSS and RFS were 87.5% and 93.3% respectively. Conclusions: In our experience, patients with PSM after PN can be managed conservatively with satisfactory long-term oncological outcomes. © 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 Please cite this article as: Fernández-Concha Schwalb JJ, Pérez Reggeti JI, López Costea MA, Bonet Puntí X, Ramos Reina H, Vigués Julia F. Márgenes positivos tras nefrectomía parcial en carcinoma de células renales: seguimiento a largo plazo y resultados oncológicos con manejo conservador. Actas Urol Esp. 2019;43:414---418. ∗ Corresponding author. E-mail address: [email protected] (J.J. Fernández-Concha Schwalb).
2173-5786/© 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Positive margins after partial nephrectomy in renal cell carcinoma
PALABRAS CLAVE Nefrectomía parcial; Carcinoma renal; Márgenes positivos
415
Márgenes positivos tras nefrectomía parcial en carcinoma de células renales: seguimiento a largo plazo y resultados oncológicos con manejo conservador Resumen Introducción: La nefrectomía parcial (NP) es el tratamiento de elección para el tumor renal peque˜ no y localizado (cT1). Uno de los puntos de debate respecto a esta técnica es el manejo de los márgenes de resección afectados/positivos (MP). Presentamos los resultados oncológicos a largo plazo en pacientes con MP tras NP manejados conservadoramente. no 1990 y 2011 se realizaron 207 NP, de las Material y métodos: En nuestro centro entre el a˜ cuales 17 tuvieron MP. Dos pacientes fueron excluidos del estudio por nefrectomía radical posterior. El seguimiento se realizó con tomografía computarizada cada 6 meses en los primeros 2 a˜ nos y luego anualmente. La supervivencia cáncer-específica y supervivencia libre de enfermedad fueron calculadas con el método de Kaplan-Meier. Resultados: La mediana de edad fue de 62 a˜ nos (RIQ: 55-71) y el tama˜ no tumoral promedio fue de 34,8 (10-77) mm. Los resultados histopatológicos fueron: 6 (40%) CCR de células claras, 4 (26,7%) papilares, 3 (20%) cromófobos y 2 (13,3%) oncocíticos. Los estadios histopatológicos fueron: 11 (73,3%) pT1a, 1 (6,7%) pT1b y 3 (20%) pT3a. La mediana de seguimiento fue de 84 meses (RIQ 72-120). Dos pacientes presentaron recidiva metastásica y muerte a causa de la misma. El primero recidivó a los 112 meses y el segundo a los 59. La supervivencia cáncerespecífica a 5 a˜ nos fue de 87,5% y la supervivencia libre de enfermedad a 5 a˜ nos fue de 93,3%. Conclusiones: En nuestra experiencia, pacientes con MP tras NP pueden ser manejados de manera conservadora, obteniendo resultados oncológicos aceptables a largo plazo. © 2019 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Nowadays, partial nephrectomy (PN) is considered the standard treatment for small, localized renal tumors (cT1).1---3 Several studies have shown that it is similar to radical nephrectomy in terms of oncological outcomes. It has shown to provide a better long-term renal function and, therefore, a lower risk of developing chronic kidney disease and hypertension in the future, thus increasing life expectancy. However, one of the risks of nephron-sparing surgery is the possibility of obtaining positive surgical margins (PM), which increases the risk of local recurrence of the disease.4 Nonetheless, some authors have questioned the fact that PM means that the tumor persists in the resection bed,5 concluding that it is not necessarily this way. Moreover, it is almost impossible to determine the cause of local recurrence: it may be due to an incomplete resection, multifocal disease (more typical of papillary renal cell carcinoma) already present at the time of surgery, or a de novo metachronous neoformation. The incidence of PM after PN ranges between 0 and 7% according to different studies,6 and it may vary based on certain tumor pathological features.7 As long as the excised tumor is surrounded by healthy renal parenchyma at the end of the nephrectomy bed, the desired safety margin is still under debate, but a minimum margin seems to be sufficient.8 This group of patients has received different therapeutic managements, ranging from observation to radical nephrectomy. However, the ideal treatment is still a matter of controversy. In this study we present the long-term oncological results of patients with PM after PN for the treatment of renal cell carcinoma (RCC). This article is an extended
version of the original publication by López Costea et al.,9 with an increased number of patients and longer follow-up.
Material and methods This is an observational, descriptive and retrospective study performed in our center from 1990 to 2011. It includes 207 PNs. There were 153 (73.9%) cases with a hystopathology result of malignant tumor and 17 (11.1%) had PM. Since two patients were excluded from the study for subsequently undergoing radical nephrectomy (one of them due to hemorrhage refractory to conservative treatment, and the other one for individual preference), it finally included 15 patients. Of the total 153 who received PN for the treatment of malignant lesions, 111 (72.5%) cases were treated by lumbotomy and the other 42 (27.5%) by transperitoneal laparoscopy. Laparoscopic PN was introduced in our center in 2006---2007, so most lumbotomies for PN were performed before 2006, and nearly all PNs from 2007 onwards were performed by laparoscopy. Hilar clamping was required in 129 (84.3%) cases and the remaining 24 (15.7%) were performed without ischemia. In most cases, the surgical technique for the tumor excision was performed with a safety margin of 2---4 mm. The tumorectomy bed and the tumor were evaluated for any suspicious area of incomplete resection or capsular disruption. In this case, a frozen section biopsy was performed to confirm the total excision. Finally, hemostasis was carried out with argon scalpel and the sliding-clip technique was performed for the hemostatic sutures of the tumor bed. A PM was defined as cancer cells at the edge of the tissue removed in the final biopsy. However, it was considered
416
J.J. Fernández-Concha Schwalb et al.
Table 1
Patient characteristics.
Case Age IQ (years)
Indication
Approach Tumor size (mm) Tumoral (mm)
Histopathology Stage pathological
Fuhrman Recurrence Follow-up (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Elective Elective Elective Solitary kidney Elective Elective CKD Elective Elective Elective Elective Solitary kidney CKD Solitary kidney Solitary kidney
Open Lap Lap Lap Open Open Lap Open Open Open Lap Open Open Open Open
Chromophobe Chromophobe Papillary Clear cell Chromophobe Papillary Clear cell Papillary Clear cell Oncocytic Papillary Clear cell Clear cell Oncocytic Clear cell
2 2 2 3 3 2 2 3 2 2 2 3 2 2 3
37 20 36 77 30 10 35 35 27 44 40 17 55 25 34
negative when the initial intraoperative (macroscopic) PM was free in the frozen section biopsy of the tumorectomy bed. All patients with PM had a minimum follow-up of 60 months (surgeries performed from 2012 onwards were not included). It involved abdominal computed tomography with contrast every 6 months for the first two years and once a year thereafter. If the patient was free of recurrence after 5 years of follow-up, the annual follow-up included alternated computed tomography and abdominal ultrasound. The Kaplan---Meier method was used to calculate oncological outcomes, cancer-specific survival and disease-free survival.
Results
pT1a pT1a pT1a pT3a pT1a pT1a pT1a pT1a pT1a pT1b pT1a pT1a pT3a pT1a pT3a
63 63 69 72 73 73 81 84 84 110 114 120 127 188 198
Survival function
1,0
Censored
0,8
0,6
87,5% a 5 años 0,4
0,2
0,0 0
The median age was 62 years (IQR: 55---71) and the average tumor size was 34.8 (10---77) mm. Regarding the histopathology of the tumors, clear cell RCC prevailed with 6 cases (40%) among the total of 15 patients. The second most frequent type was papillary RCC with 4 cases (26.7%), followed by chromophobe in 3 cases (20%) and finally 2 oncocytic tumors (13.3%). The pathological stages were as follows: 11 (73.3%) pT1a, 1 (6.7%) pT1b and 3 (20%) pT3a. The pT3a tumors were clinically understaged cases of one initial cT1a tumor and two cT1b tumors. The Fuhrman nuclear grade was 2 in 10 cases (66.7%) and 3 in the other 5 (33.3%). The median follow-up was 84 months, ranging from 63 to 198 (IQR 72---120). Two patients presented disease recurrence and death during follow-up. One of them manifested distant recurrence at 59 months with lung, liver and bone metastases. The initial tumor was a Fuhrman 2, pT1a clear cell RCC. This patient received systemic treatment and died at 84 months of follow-up. The second patient presented systemic recurrence at 112 months after surgery, with pulmonary metastases. In this case, the initial tumor was a Fuhrman 3, pT3a clear cell RCC. This patient underwent systemic treatment and died after 198 months of follow-up. The characteristics of the 15 patients are summarized in Table 1.
No No No No No No No No 59 months No No No No No 112 months
Cancer-specific survival
Cumulative survival
61 50 66 55 74 57 75 45 77 68 62 71 70 60 45
50
100
150
200
Time (months)
Figure 1
Cancer-specific survival calculated at 5 years.
Cancer-specific survival and disease-free survival at 5 years, calculated using the Kaplan---Meier method, were 87.5% and 93.3% respectively. Both graphs are shown in Figs. 1 and 2, respectively.
Discussion Although PN is becoming increasingly popular for the treatment of RCC, the potential risk of residual disease must be addressed carefully. This is why there are several studies that attempt to clarify the prognostic impact of PM. Some authors suggest that PM do not necessarily imply persistent disease in the renal remnant. Sundaram et al.5 conducted a study with 29 patients with PM after PN to determine if there was really tumor tissue remaining in the renal bed of the tumorectomy. All the patients presenting PM underwent surgery by radical nephrectomy (8 patients) or margin resection (21 patients). None of the 8 patients who received
Positive margins after partial nephrectomy in renal cell carcinoma Disease-free survival Survival function
1,0
Censored
Cumulative survival
0,8
0,6
93,3% a 5 años 0,4
0,2
0,0 0
50
100
150
200
Time (months)
Figure 2
Disease-free survival calculated at 5 years.
radical nephrectomy showed residual disease and only 2 of the 21 who underwent marginal resection had residual carcinoma. In a similar way, none of the two patients with PM excluded from the study for receiving radical nephrectomy presented residual disease in their last pathology report. Although the prognostic impact of PM on RCC is different from other types of tumors, it is imperative to use strategies to prevent it and, at the same time, avoid the risk of local recurrence. Some of these strategies include: (i) the use of endocavitary ultrasound for and improved delimitation of the tumor margins, especially in highly endophytic masses10 ; (ii) hilar clamping, which provides differentiation between the tumor and the caliceal system.11 Yossepovitch et al.12 obtained more PM in the smallest renal masses. This could be due to a less clear delimitation of healthy tissue in these tumors. (iii) Finally, some hemostatic procedures performed on the resection bed, such as the use of the argon or ultrasonic scalpel, could destroy residual tumor cells. Also, the application of different hemostatic materials could obtain the same result through inflammatory reactions.13,14 Among other causes for local recurrence which are not related to the presence of PM, the existence of tumor multifocality should be considered, especially in papillary CRC. López-Costea et al.15 published an article in 2016 analyzing the prognostic factors in 198 partial nephrectomies. A clear predictor of PM was not identified. However, the highest R.E.N.A.L. score showed a non-statistically significant trend (p = 0.13) toward the risk of presenting PM. Only 42 out of 198 patients had the R.E.N.A.L. score calculated, and 9 of them had PM. Although these data are not conclusive, this could be due to the low statistical power of the series. Regarding prognostic factors for recurrence, there is only one evaluation of the whole series, but not of the subgroup of PM patients, and they found that bilateral tumors and an imperative indication for nephron-sparing surgery (solitary kidney, bilateral tumors, chronic kidney disease) were statistically significant in the bivariate analysis (p = 0.03 and p = 0.05 respectively). In our study, one of the (2) patients who had recurrence had elective indication and the other one, imperative (solitary kidney). To date, there is no clear evidence that a peritumoral margin of healthy tissue is better than the minimum one.16 A few mm of healthy parenchyma are considered oncologically
417
acceptable. Although we used to perform frozen section biopsy for the analysis of suspicious residual areas in the tumorectomy bed, there is little evidence that this procedure is superior to one single macroscopic impression of a total excision and, at present, we have abandoned this practice.17 The therapeutic options for PM after PN vary from observation to radical nephrectomy as the most aggressive option, with radiofrequency and margin re-resection as intermediate alternatives. However, given the low incidence of tumor recurrence in this group of patients, most studies support the more conservative management, which is observation.12,18---20 However, there is also significant variability between patients and tumors, mainly from a histological point of view. Some tumors have a low malignant potential (papillary type 1, oncocytic and chromophobe), while others have a higher potential (clear cell, papillary type 2 and tumors with sarcomatoid differentiation). Therefore, these factors must be taken into account when establishing the protocol for patient monitoring. Shah et al.7 published a study including 1240 patients with PM. They performed a multivariate analysis with two subgroups of patients: low and high risk. The low-risk group corresponded to pT1 and Fuhrman 1 and 2 tumors, while the high-risk group comprised pT2-3a or Fuhrman 3 and 4 tumors. The high-risk group had a considerably higher recurrence probability (HR 7.48, 95% CI 2.75---20.34; p < 0.001) compared to the low-risk (HR 0.62, 95% CI 0.08---4.75; p = 0.647). With these results, it seems logical to think that PM should not be considered a definitive factor for the management of a patient. Other criteria, such as anatomopathological features of each tumor, should be taken into account. However, the presence of PM and/or unfavorable histology is not enough to attribute recurrence to an incomplete tumorectomy. The chances of unknown tumor multifocality may always exist, and this variable is not always under control. We must mention that one of the two patients who presented recurrence in our series had an imperative indication for PN due to a previous radical nephrectomy for a clear cell CRC pT3b. Therefore, we cannot determine if recurrence was due to the first or second tumor.
Conclusions In our experience, patients with PM after PN can be managed conservatively with acceptable long-term oncological outcomes, avoiding additional costs and adverse effects from more aggressive treatments.
Conflicts of interest The authors declare that they have no conflicts of interest.
References 1. Patard JJ, Shvarts O, Lam JS, Pantuck AJ, Kim HL, Ficarra V, et al. Safety and efficacy of partial nephrectomy for all T1 tumors based on an international multicenter experience. J Urol. 2004;171:2181 [PubMed: 15126781]. 2. Weight CG, Larson BT, Fergany AF, Gao T, Lane BR, Campbell SC, et al. Nephrectomy induced chronic renal insufficiency is
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3.
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9.
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J.J. Fernández-Concha Schwalb et al. associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol. 2010;183:1317---23. Leibovich BC, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol. 2004;171:1066 [PubMed: 14767272]. Kwon EO, Carver BS, Snyder ME, Russo P. Impact of positive surgical margins in patients undergoing partial nephrectomy for renal cortical tumours. BJU Int. 2007;99:286---9. Sundaram V, Figenshau RS, Roytman TM, Kibel AS, Grubb RL, Bullock A, et al. Positive margin during partial nephrectomy: does cancer remain in the renal remnant? Urology. 2011;77:1400---3. Borghesi M, Brunocilla E, Schiavina R, Martorana G. Positive surgical margins after nephron-sparing surgery for renal cell carcinoma: incidence, clinical impact, and management. Clin Genitourin Cancer. 2013;11:5---9. Shah PH, Moreira DM, Okhunov Z, Patel VR, Chopra S, Razmaria AA, et al. Positive surgical margins increase risk of recurrence after partial nephrectomy for high risk renal tumors. J Urol. 2016;196:327---34. Timsit MO, Bazin JP, Thiounn N, Fontaine E, Chretien Y, Dufour B, et al. Prospective study of safety margins in partial nephrectomy: intraoperative assessment and contribution of frozen section analysis. Urology. 2006;67:923 [PubMed: 16635521]. López-Costea MA, Fumadó L, Lorente D, Riera L, Miranda EF. Positive margins after nephron-sparing surgery for renal cell carcinoma: long-term follow-up of patients on active surveillance. BJU Int. 2010;106:645---8. Nguyen TT, Parkinson JP, Kuehn DM, Winfield HN. Technique for ensuring negative surgical margins during laparoscopic partial nephrectomy. J Endourol. 2005;19:410---5. Gill IS, Desai MM, Kaouk JH, Meraney AM, Murphy DP, Sung GT, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol. 2002;167:469---77.
12. Yossepowitch O, Houston Thompson R, Leibovich BC, Eggener SE, Pettus JA, Kwon ED, et al. Predictors and oncological outcomes following positive surgical margins at partial nephrectomy. J Urol. 2008;179:2158---63. 13. Lam JS, Bergman J, Breda A, Schulam PG. Importance of surgical margins in the management of renal cell carcinoma. Nat Clin Pract Urol. 2008;5:308---17. 14. Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol. 2006;175:425---31. 15. López-Costea MA, Bonet X, Pérez-Reggeti J, Etcheverry B, Vigués F. Oncological outcomes and prognostic factors after nephron-sparing surgery in renal cell carcinoma. Int Urol Nephrol. 2016;48:681---6. 16. Li QL, Guan HW, Zhang QP, Zhang LZ, Wang FP, Liu YJ. Optimal margin in nephron-sparing surgery for renal cell carcinoma 4 cm or less. Eur Urol. 2003;44:448---51. 17. Marszalek M, Carini M, Chlosta P, Jeschke K, Kirkali Z, Knüchel R, et al. Positive surgical margins after nephron-sparing surgery. Eur Urol. 2012;61:757---63. 18. Breda A, Stepanian SV, Liao J, Lam JS, Guazzoni G, Stifelman M, et al. Positive margins in laparoscopic partial nephrectomy in 855 cases: a multi-institutional survey from the United States and Europe. J Urol. 2007;178:47---50. 19. Permpongkosol S, Colombo JR Jr, Gill IS, Kavoussi LR. Positive surgical parenchymal margin after laparoscopic partial nephrectomy for renal cell carcinoma: oncological outcomes. J Urol. 2006;176:2401---4. 20. Steinestel J, Steffens S, Steinestel K, Schrader AJ. Positive surgical margins in nephron-sparing surgery: risk factors and therapeutic consequences. World J Surg Oncol. 2014; 12:252.
Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro
ORIGINAL ARTICLE
Positive margins after partial nephrectomy in renal cell carcinoma: Oncological outcomes of conservative management after long-term follow-up夽 J.J. Fernández-Concha Schwalb ∗ , J.I. Pérez Reggeti, M.A. López Costea, X. Bonet Puntí, H. Ramos Reina, F. Vigués Julia Servicio de Urología, Hospital Universitario de Bellvitge, Barcelona, Spain Received 14 January 2019; accepted 4 March 2019 Available online 20 September 2019
KEYWORDS Partial nephrectomy; Renal cell carcinoma; Positive margins
Abstract Introduction: Partial nephrectomy (PN) is the standard treatment for small and localized kidney tumors (cT1). One of the controversial aspects regarding this technique is the management of affected/positive resection margins. We present the long-term oncological results in patients with PSM after PN managed conservatively. Material and methods: There were 207 PN performed in our center between 1990 and 2011. 17 patients presented PSM. 2 patients were excluded from the study due to completion nephrectomy afterwards. Follow-up was done with abdominal contrast-enhanced computed tomography every 6 months for the first 2 years and subsequently, once a year. Cancer-specific survival and disease-free survival were calculated with the Kaplan---Meier method. Results: The median age was 62 years (RIQ: 55---71) and the mean tumor size was 34.8 (10---77) mm. Histopathological results were: 6 (40%) clear cell RCC, 4 (26.7%) papillary, 3 (20%) chromophobe and 2 (13.3%) oncocytic. The pathologic stages were: 11 (73.3%) pT1a, 1 (6.7%) pT1b and 3 (20%) pT3a. The median follow-up was 84 months (IQR 72---120). 2 patients had metastatic recurrence and this was the cause of death. The first one had recurrence at 112 months and the second one at 59. 5-year CSS and RFS were 87.5% and 93.3% respectively. Conclusions: In our experience, patients with PSM after PN can be managed conservatively with satisfactory long-term oncological outcomes. © 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 Please cite this article as: Fernández-Concha Schwalb JJ, Pérez Reggeti JI, López Costea MA, Bonet Puntí X, Ramos Reina H, Vigués Julia F. Márgenes positivos tras nefrectomía parcial en carcinoma de células renales: seguimiento a largo plazo y resultados oncológicos con manejo conservador. Actas Urol Esp. 2019;43:414---418. ∗ Corresponding author. E-mail address: [email protected] (J.J. Fernández-Concha Schwalb).
2173-5786/© 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Positive margins after partial nephrectomy in renal cell carcinoma
PALABRAS CLAVE Nefrectomía parcial; Carcinoma renal; Márgenes positivos
415
Márgenes positivos tras nefrectomía parcial en carcinoma de células renales: seguimiento a largo plazo y resultados oncológicos con manejo conservador Resumen Introducción: La nefrectomía parcial (NP) es el tratamiento de elección para el tumor renal peque˜ no y localizado (cT1). Uno de los puntos de debate respecto a esta técnica es el manejo de los márgenes de resección afectados/positivos (MP). Presentamos los resultados oncológicos a largo plazo en pacientes con MP tras NP manejados conservadoramente. no 1990 y 2011 se realizaron 207 NP, de las Material y métodos: En nuestro centro entre el a˜ cuales 17 tuvieron MP. Dos pacientes fueron excluidos del estudio por nefrectomía radical posterior. El seguimiento se realizó con tomografía computarizada cada 6 meses en los primeros 2 a˜ nos y luego anualmente. La supervivencia cáncer-específica y supervivencia libre de enfermedad fueron calculadas con el método de Kaplan-Meier. Resultados: La mediana de edad fue de 62 a˜ nos (RIQ: 55-71) y el tama˜ no tumoral promedio fue de 34,8 (10-77) mm. Los resultados histopatológicos fueron: 6 (40%) CCR de células claras, 4 (26,7%) papilares, 3 (20%) cromófobos y 2 (13,3%) oncocíticos. Los estadios histopatológicos fueron: 11 (73,3%) pT1a, 1 (6,7%) pT1b y 3 (20%) pT3a. La mediana de seguimiento fue de 84 meses (RIQ 72-120). Dos pacientes presentaron recidiva metastásica y muerte a causa de la misma. El primero recidivó a los 112 meses y el segundo a los 59. La supervivencia cáncerespecífica a 5 a˜ nos fue de 87,5% y la supervivencia libre de enfermedad a 5 a˜ nos fue de 93,3%. Conclusiones: En nuestra experiencia, pacientes con MP tras NP pueden ser manejados de manera conservadora, obteniendo resultados oncológicos aceptables a largo plazo. © 2019 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Nowadays, partial nephrectomy (PN) is considered the standard treatment for small, localized renal tumors (cT1).1---3 Several studies have shown that it is similar to radical nephrectomy in terms of oncological outcomes. It has shown to provide a better long-term renal function and, therefore, a lower risk of developing chronic kidney disease and hypertension in the future, thus increasing life expectancy. However, one of the risks of nephron-sparing surgery is the possibility of obtaining positive surgical margins (PM), which increases the risk of local recurrence of the disease.4 Nonetheless, some authors have questioned the fact that PM means that the tumor persists in the resection bed,5 concluding that it is not necessarily this way. Moreover, it is almost impossible to determine the cause of local recurrence: it may be due to an incomplete resection, multifocal disease (more typical of papillary renal cell carcinoma) already present at the time of surgery, or a de novo metachronous neoformation. The incidence of PM after PN ranges between 0 and 7% according to different studies,6 and it may vary based on certain tumor pathological features.7 As long as the excised tumor is surrounded by healthy renal parenchyma at the end of the nephrectomy bed, the desired safety margin is still under debate, but a minimum margin seems to be sufficient.8 This group of patients has received different therapeutic managements, ranging from observation to radical nephrectomy. However, the ideal treatment is still a matter of controversy. In this study we present the long-term oncological results of patients with PM after PN for the treatment of renal cell carcinoma (RCC). This article is an extended
version of the original publication by López Costea et al.,9 with an increased number of patients and longer follow-up.
Material and methods This is an observational, descriptive and retrospective study performed in our center from 1990 to 2011. It includes 207 PNs. There were 153 (73.9%) cases with a hystopathology result of malignant tumor and 17 (11.1%) had PM. Since two patients were excluded from the study for subsequently undergoing radical nephrectomy (one of them due to hemorrhage refractory to conservative treatment, and the other one for individual preference), it finally included 15 patients. Of the total 153 who received PN for the treatment of malignant lesions, 111 (72.5%) cases were treated by lumbotomy and the other 42 (27.5%) by transperitoneal laparoscopy. Laparoscopic PN was introduced in our center in 2006---2007, so most lumbotomies for PN were performed before 2006, and nearly all PNs from 2007 onwards were performed by laparoscopy. Hilar clamping was required in 129 (84.3%) cases and the remaining 24 (15.7%) were performed without ischemia. In most cases, the surgical technique for the tumor excision was performed with a safety margin of 2---4 mm. The tumorectomy bed and the tumor were evaluated for any suspicious area of incomplete resection or capsular disruption. In this case, a frozen section biopsy was performed to confirm the total excision. Finally, hemostasis was carried out with argon scalpel and the sliding-clip technique was performed for the hemostatic sutures of the tumor bed. A PM was defined as cancer cells at the edge of the tissue removed in the final biopsy. However, it was considered
416
J.J. Fernández-Concha Schwalb et al.
Table 1
Patient characteristics.
Case Age IQ (years)
Indication
Approach Tumor size (mm) Tumoral (mm)
Histopathology Stage pathological
Fuhrman Recurrence Follow-up (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Elective Elective Elective Solitary kidney Elective Elective CKD Elective Elective Elective Elective Solitary kidney CKD Solitary kidney Solitary kidney
Open Lap Lap Lap Open Open Lap Open Open Open Lap Open Open Open Open
Chromophobe Chromophobe Papillary Clear cell Chromophobe Papillary Clear cell Papillary Clear cell Oncocytic Papillary Clear cell Clear cell Oncocytic Clear cell
2 2 2 3 3 2 2 3 2 2 2 3 2 2 3
37 20 36 77 30 10 35 35 27 44 40 17 55 25 34
negative when the initial intraoperative (macroscopic) PM was free in the frozen section biopsy of the tumorectomy bed. All patients with PM had a minimum follow-up of 60 months (surgeries performed from 2012 onwards were not included). It involved abdominal computed tomography with contrast every 6 months for the first two years and once a year thereafter. If the patient was free of recurrence after 5 years of follow-up, the annual follow-up included alternated computed tomography and abdominal ultrasound. The Kaplan---Meier method was used to calculate oncological outcomes, cancer-specific survival and disease-free survival.
Results
pT1a pT1a pT1a pT3a pT1a pT1a pT1a pT1a pT1a pT1b pT1a pT1a pT3a pT1a pT3a
63 63 69 72 73 73 81 84 84 110 114 120 127 188 198
Survival function
1,0
Censored
0,8
0,6
87,5% a 5 años 0,4
0,2
0,0 0
The median age was 62 years (IQR: 55---71) and the average tumor size was 34.8 (10---77) mm. Regarding the histopathology of the tumors, clear cell RCC prevailed with 6 cases (40%) among the total of 15 patients. The second most frequent type was papillary RCC with 4 cases (26.7%), followed by chromophobe in 3 cases (20%) and finally 2 oncocytic tumors (13.3%). The pathological stages were as follows: 11 (73.3%) pT1a, 1 (6.7%) pT1b and 3 (20%) pT3a. The pT3a tumors were clinically understaged cases of one initial cT1a tumor and two cT1b tumors. The Fuhrman nuclear grade was 2 in 10 cases (66.7%) and 3 in the other 5 (33.3%). The median follow-up was 84 months, ranging from 63 to 198 (IQR 72---120). Two patients presented disease recurrence and death during follow-up. One of them manifested distant recurrence at 59 months with lung, liver and bone metastases. The initial tumor was a Fuhrman 2, pT1a clear cell RCC. This patient received systemic treatment and died at 84 months of follow-up. The second patient presented systemic recurrence at 112 months after surgery, with pulmonary metastases. In this case, the initial tumor was a Fuhrman 3, pT3a clear cell RCC. This patient underwent systemic treatment and died after 198 months of follow-up. The characteristics of the 15 patients are summarized in Table 1.
No No No No No No No No 59 months No No No No No 112 months
Cancer-specific survival
Cumulative survival
61 50 66 55 74 57 75 45 77 68 62 71 70 60 45
50
100
150
200
Time (months)
Figure 1
Cancer-specific survival calculated at 5 years.
Cancer-specific survival and disease-free survival at 5 years, calculated using the Kaplan---Meier method, were 87.5% and 93.3% respectively. Both graphs are shown in Figs. 1 and 2, respectively.
Discussion Although PN is becoming increasingly popular for the treatment of RCC, the potential risk of residual disease must be addressed carefully. This is why there are several studies that attempt to clarify the prognostic impact of PM. Some authors suggest that PM do not necessarily imply persistent disease in the renal remnant. Sundaram et al.5 conducted a study with 29 patients with PM after PN to determine if there was really tumor tissue remaining in the renal bed of the tumorectomy. All the patients presenting PM underwent surgery by radical nephrectomy (8 patients) or margin resection (21 patients). None of the 8 patients who received
Positive margins after partial nephrectomy in renal cell carcinoma Disease-free survival Survival function
1,0
Censored
Cumulative survival
0,8
0,6
93,3% a 5 años 0,4
0,2
0,0 0
50
100
150
200
Time (months)
Figure 2
Disease-free survival calculated at 5 years.
radical nephrectomy showed residual disease and only 2 of the 21 who underwent marginal resection had residual carcinoma. In a similar way, none of the two patients with PM excluded from the study for receiving radical nephrectomy presented residual disease in their last pathology report. Although the prognostic impact of PM on RCC is different from other types of tumors, it is imperative to use strategies to prevent it and, at the same time, avoid the risk of local recurrence. Some of these strategies include: (i) the use of endocavitary ultrasound for and improved delimitation of the tumor margins, especially in highly endophytic masses10 ; (ii) hilar clamping, which provides differentiation between the tumor and the caliceal system.11 Yossepovitch et al.12 obtained more PM in the smallest renal masses. This could be due to a less clear delimitation of healthy tissue in these tumors. (iii) Finally, some hemostatic procedures performed on the resection bed, such as the use of the argon or ultrasonic scalpel, could destroy residual tumor cells. Also, the application of different hemostatic materials could obtain the same result through inflammatory reactions.13,14 Among other causes for local recurrence which are not related to the presence of PM, the existence of tumor multifocality should be considered, especially in papillary CRC. López-Costea et al.15 published an article in 2016 analyzing the prognostic factors in 198 partial nephrectomies. A clear predictor of PM was not identified. However, the highest R.E.N.A.L. score showed a non-statistically significant trend (p = 0.13) toward the risk of presenting PM. Only 42 out of 198 patients had the R.E.N.A.L. score calculated, and 9 of them had PM. Although these data are not conclusive, this could be due to the low statistical power of the series. Regarding prognostic factors for recurrence, there is only one evaluation of the whole series, but not of the subgroup of PM patients, and they found that bilateral tumors and an imperative indication for nephron-sparing surgery (solitary kidney, bilateral tumors, chronic kidney disease) were statistically significant in the bivariate analysis (p = 0.03 and p = 0.05 respectively). In our study, one of the (2) patients who had recurrence had elective indication and the other one, imperative (solitary kidney). To date, there is no clear evidence that a peritumoral margin of healthy tissue is better than the minimum one.16 A few mm of healthy parenchyma are considered oncologically
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acceptable. Although we used to perform frozen section biopsy for the analysis of suspicious residual areas in the tumorectomy bed, there is little evidence that this procedure is superior to one single macroscopic impression of a total excision and, at present, we have abandoned this practice.17 The therapeutic options for PM after PN vary from observation to radical nephrectomy as the most aggressive option, with radiofrequency and margin re-resection as intermediate alternatives. However, given the low incidence of tumor recurrence in this group of patients, most studies support the more conservative management, which is observation.12,18---20 However, there is also significant variability between patients and tumors, mainly from a histological point of view. Some tumors have a low malignant potential (papillary type 1, oncocytic and chromophobe), while others have a higher potential (clear cell, papillary type 2 and tumors with sarcomatoid differentiation). Therefore, these factors must be taken into account when establishing the protocol for patient monitoring. Shah et al.7 published a study including 1240 patients with PM. They performed a multivariate analysis with two subgroups of patients: low and high risk. The low-risk group corresponded to pT1 and Fuhrman 1 and 2 tumors, while the high-risk group comprised pT2-3a or Fuhrman 3 and 4 tumors. The high-risk group had a considerably higher recurrence probability (HR 7.48, 95% CI 2.75---20.34; p < 0.001) compared to the low-risk (HR 0.62, 95% CI 0.08---4.75; p = 0.647). With these results, it seems logical to think that PM should not be considered a definitive factor for the management of a patient. Other criteria, such as anatomopathological features of each tumor, should be taken into account. However, the presence of PM and/or unfavorable histology is not enough to attribute recurrence to an incomplete tumorectomy. The chances of unknown tumor multifocality may always exist, and this variable is not always under control. We must mention that one of the two patients who presented recurrence in our series had an imperative indication for PN due to a previous radical nephrectomy for a clear cell CRC pT3b. Therefore, we cannot determine if recurrence was due to the first or second tumor.
Conclusions In our experience, patients with PM after PN can be managed conservatively with acceptable long-term oncological outcomes, avoiding additional costs and adverse effects from more aggressive treatments.
Conflicts of interest The authors declare that they have no conflicts of interest.
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